The relative risk of developing a mental illness or neurological disorder varies considerably by gender. Males exhibit far higher rates of autism and autism spectrum disorder, Tourette's Syndrome, stuttering, dyslexia, and early onset of schizophrenia, all of which have a childhood onset. In contrast, females suffer much higher incidences of major depressive disorders, general anxiety disorder, anorexia, bulimia, and late onset of schizophrenia, all of which have adult onsets. The biological basis for these gender biases is entirely unknown. By exploring how the brain develops differently in males and females, using a mammalian animal model, we can gain insight into the potential sources of the sex differences in disease and identify potential therapeutic and preventive targets. Moreover, the hippocampus is a brain region of particular interest because of its central role in learning and memory, including social communication, and in regulating the response to stress. In addition, pathologies of the hippocampus are associated with numerous mental health disorders. The current proposal focuses on the early postnatal development of the hippocampus in males versus females and how this development is impacted by the endogenous steroid, estradiol. Previous observations reveal newborn males generate more new hippocampal cells than females, furthermore, the number of new cells can be increased in females by exogenous estradiol treatment (Zhang et al., 2008). We now build on this finding by testing two specific hypotheses. Hypothesis #1: Estradiol increases cell proliferation in the neonatal hippocampus, will be tested by experiments that distinguish cell proliferation from cell survival. Hypothesis #2: Estradiol promotes neuronal/glial proliferation and/or survival in the neonatal hippocampus as a result of enhancing depolarizing GABA action, will build on Hypothesis #1 by determining whether the new cells become neurons or glia and if this endpoint depends on our previously documented estradiol-induced enhancement of excitatory actions of GABA. Results from these experiments will form the foundation for an integrated view of how gender and estradiol coordinate hippocampal development differently in males and females to alter neuronal functioning and ultimately behavior. Given the central role of the hippocampus in many affective disorders, these results will provide insights into the origins of mental illness as well as normal cognitive functioning. PUBLIC HEALTH RELEVANCE: The risk of developing a mental illness or neurological disorder varies considerably by gender. Thus, the current proposal focuses on how the brain develops differently in males and females. By exploring sex differences in brain development, it will be possible to gain insight into the potential sources of the sex differences in disease along with identifying potential therapeutic and preventative treatments.